Structures of teixobactin-producing nonribosomal peptide synthetase condensation and adenylation domains

Curr Res Struct Biol. 2020 Feb 5;2:14-24. doi: 10.1016/j.crstbi.2020.01.002. eCollection 2020.


The recently discovered antibiotic teixobactin is produced by uncultured soil bacteria. The antibiotic inhibits cell wall synthesis of Gram-positive bacteria by binding to precursors of cell wall building blocks, and therefore it is thought to be less vulnerable to development of resistance. Teixobactin is synthesized by two nonribosomal peptide synthetases (NRPSs), encoded by txo1 and txo2 genes. Like other NRPSs, the Txo1 and Txo2 synthetases are large, multifunctional, and comprised of several modules. Each module is responsible for catalysis of a distinct step of teixobactin synthesis and contains specific functional units, commonly including a condensation (C) domain, an adenylation (A) domain, and a peptidyl carrier protein (PCP) domain. Here we report the structures of the C-A bidomains of the two L-Ser condensing modules, from Txo1 and Txo2, respectively. In the structure of the C domain of the L-Ser subunit of Txo1, a large conformational change is observed, featuring an outward swing of its N-terminal α-helix. This repositioning, if functionally validated, provides the necessary conformational change for the condensation reaction in C domain, and likely represents a regulatory mechanism. In an Acore subdomain, a well-coordinated Mg2+ cation is observed, which is required in the adenylation reaction. The Mg2+-binding site is defined by a largely conserved amino acid sequence motif and is coordinated by the α-phosphate group of AMP (or ATP) when present, providing some structural evidence for the role of the metal cation in the catalysis of A domain.

Keywords: A domain, Adenylation domain; Acore subdomain, Large N-terminal subdomain of A domain; Adenylation domain; Asub subdomain, Small C-terminal subdomain of A domain; C domain, Condensation domain; CCterm subdomain, C-terminal subdomain of C domain; CNterm subdomain, N-terminal subdomain of C domain; COMA domain, Acceptor communication-mediating domain; COMD domain, Donor communication-mediating domain; Condensation domain; Conformational change; MES, 2- morpholinoethane sulfonic acid; Mg2+-binding; NRPS, Nonribosomal peptide synthetase; Nonribosomal peptide synthetase; PCP domain, Peptidyl carrier domain; RMSD, Root-mean-square deviation; SAD, Single wavelength diffraction; SSM, Secondary-structure matching; Teixobactin; Txo1; Txo2; α-helix regulation.